Effect of blood product medium supplements on the activity of cefotaxime and other cephalosporins against Enterococcus faecalis.

The activities of cefotaxime and other aminothiazoyl oxime cephalosporins against Enterococcus faecalis were enhanced by addition of 5% sheep blood to Mueller-Hinton agar. This effect was not seen with aztreonam (aminothiazoyl oxime monobactam), cefotiam (aminothiazoyl, nonoxime), or other cephalosporins, and it was specific to the syn-configuration of the oxime moiety. Enhancement of cefotaxime activity was demonstrable against approximately 50% of 86 clinical isolates and could only be shown at low bacterial inocula. Human serum, serum alpha 1-, beta- and gamma-globulin fractions and albumin often antagonized or did not affect significantly the antimicrobial activity of cefotaxime, while the alpha 2-globulin fraction usually enhanced drug activity. The in vivo activity of cefotaxime against E. faecalis was examined in a rat peritoneal abscess model. The test organism was resistant to cefotaxime by standard methods (MIC greater than 128 micrograms/ml) but was inhibited by 1.0 microgram/ml when rat serum was presented in the medium. Cefotaxime reduced titers of bacteria within abscesses after 5 days of therapy (5.77 +/- 0.68 log10 CFU/g) in comparison with those in control animals (7.38 +/- 0.28 log10 CFU/g, p less than 0.05). Moxalactam, the in vitro activity of which was not augmented by serum, proved ineffective in the animal model. While these observations do not have direct therapeutic relevance, they offer a possible explanation for the relatively infrequent occurrence of enterococcal superinfection in patients treated with cefotaxime.

High-level resistance to gentamicin in clinical isolates of Streptococcus (Enterococcus) faecium.

During a 14-month period beginning in July 1986, three distinct clinical isolates of Streptococcus (Enterococcus) faecium demonstrating high-level resistance (MIC, greater than 2,000 micrograms/ml) to gentamicin, kanamycin, tobramycin, and streptomycin were recovered from individual patients at one institution. Combinations of ampicillin with any of these agents failed to show bactericidal synergism. By filter-mating techniques, high-level gentamicin resistance could be transferred into a susceptible recipient of the same species at frequencies as high as 1 x 10(-4); transfer into Streptococcus faecalis JH2-7 occurred at lower frequencies (less than 2 x 10(-7). Aminoglycoside substrate profile analysis of clinical isolates as well as of laboratory-derived cured strains and transconjugants revealed 2"-aminoglycoside phosphotransferase and 3'-aminoglycoside phosphotransferase (III) phosphorylating enzymes, AAC-6' acetylating activity above that attributable to the intrinsic activity characteristic of S. faecium, and a streptomycin adenylylating enzyme. All three isolates carried a 51-megadalton plasmid. Curing of this plasmid or conjugative transfer into susceptible recipients was associated with the loss or acquisition of high-level gentamicin resistance, respectively. Loss of high-level gentamicin resistance was also observed when curing techniques resulted in a decrease in the size of this plasmid equivalent to a 10-megadalton deletion. Transferable, high-level resistance to gentamicin and other aminoglycosides, which was previously recognized in S. faecalis, has now emerged in clinical isolates of S. faecium, with the attendant concerns for possible spread.

Activity and mechanism of action of DuP 105 and DuP 721, new oxazolidinone compounds.

The in-vitro activities of DuP 721 and DuP 105, new oxazolidinone antibacterials, were compared with those of cefazolin, cephalexin, ciprofloxacin, clindamycin, oxacillin, penicillin, and vancomycin against Gram-positive cocci. DuP 721 was approximately four-fold more active than DuP 105 with an MIC of 2.0 mg/l for 90% of the Staphylococcus aureus, beta-haemolytic streptococcus and Streptococcus faecalis strains tested, and an MIC of 4.0 mg/l for 90% of the Str. faecium, penicillin-resistant Str. pneumoniae and viridans streptococcus strains tested. DuP 105 was most active against strains of Staph. epidermidis with an MIC of 4.0 mg/l for 90% of the strains tested. There was no cross resistance between these and the other antibacterial agents that were tested. Both oxazolidinones had bacteriostatic activity in broth against susceptible organisms. Both DuP 721 and DuP 105 inhibited ribosomal protein synthesis in a cell-free system. These synthetic, orally absorbable compounds represent a new series of antibacterial agents unrelated by chemical structure to any other currently available antimicrobial agents.

In vitro activities of ICI 194008 and ICI 193428, two new cephem antimicrobial agents.

The in vitro activities of two new cephem antibiotics, ICI 193428 and ICI 194008, were compared with those of cefpirome, cefotaxime, ceftazidime, and piperacillin. Essentially all strains of the family Enterobacteriaceae were inhibited by both study drugs at concentrations of less than or equal to 4 micrograms/ml. Both new cephems were comparable to ceftazidime against Pseudomonas aeruginosa (MIC for 90% of strains, 8 micrograms/ml) and were the most active agents tested against Pseudomonas maltophilia (MIC for 90% of strains, 16 micrograms/ml).

Comparative in-vitro activity of A-56268 (TE-031), a new macrolide antibiotic.

The comparative in-vitro activity of A-56268 (TE-031), a new semisynthetic macrolide antibiotic, was assessed against approximately 400 bacterial isolates. The new drug demonstrated excellent activity against penicillin-susceptible streptococci (MIC90s less than or equal to 0.06 mg/l) and methicillin-susceptible staphylococci (MIC90 = 0.25 mg/l). Among other Gram-positive organisms tested, a significant number were resistant to A-56268 as well as to erythromycin and clindamycin. A-56268 was at least as active as erythromycin against Pasteurella multocida and Campylobacter jejuni, but was more active than erythromycin against Legionella spp. (MIC90 less than or equal to 0.06 mg/l), Bacteroides fragilis (MIC90 = 4 mg/l) and Bact. melaninogenicus (MIC90 less than or equal to 0.125 mg/l). Activity of A-56268 was pH dependent (more active at pH 7 than at pH 6) and was moderately affected by inoculum size. The drug was bactericidal against two strains of Streptococcus pyogenes tested, but exerted a bacteriostatic effect against Staphylococcus aureus and Str. faecalis.

Comparative in vitro activity of CGP 31608, a new penem antibiotic.

The in vitro activity of a new penem antimicrobial agent, CGP 31608, was compared with those of imipenem, SCH 34343, and several other antimicrobial agents against approximately 600 bacterial isolates. CGP 31608 was active against gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MIC for 90% of the isolates [MIC90], 0.25 microgram/ml) and penicillin-susceptible streptococci (MIC90s, less than or equal to 2 micrograms/ml). Penicillin-resistant streptococci (including enterococci) and methicillin-resistant S. aureus were more resistant to the penem. Activities of CGP 31608 against members of the family Enterobacteriaceae were remarkably uniform, with MIC90s of 8 to 16 micrograms/ml. CGP 31608 was at least as active as imipenem and ceftazidime and more active than piperacillin against Pseudomonas aeruginosa. Drug activity was not influenced by the presence of any of 10 plasmid-mediated beta-lactamases. Against strains of Serratia marcescens, Enterobacter cloacae, and P. aeruginosa with derepressible chromosomally mediated beta-lactamases, the presence of cefoxitin did not induce increased resistance to CGP 31608. The new drug was also active against anaerobes (MIC90s, 0.25 to 8 micrograms/ml), Haemophilus influenzae (MIC90s, 0.5 to 1.0 micrograms/ml), and Legionella spp. (MIC90, 2 micrograms/ml). CGP 31608 showed an antibacterial spectrum similar to those of imipenem and SCH 34343 (except that the latter is not active against P. aeruginosa) but was generally less potent than these drugs. However, CGP 31608 demonstrated more activity (MIC90) than imipenem against P. aeruginosa, Pseudomonas cepacia, and methicillin-resistant Staphylococcus epidermidis and S. aureus.

In vitro evaluation of the new paulomycin antibiotic paldimycin.

The comparative in vitro activity of paldimycin, a new antibiotic, was evaluated against 215 gram-positive bacteria. Activity of the compound was greater in nutrient agar of pH 6.8 than in Mueller-Hinton agar. All strains of staphylococci, streptococci, enterococci and Listeria monocytogenes were inhibited at concentrations less than or equal to 2 micrograms/ml. Activity of the new drug was generally comparable to that of vancomycin.

In vitro activity of BMY-28100, a new oral cephalosporin.

The activity of BMY-28100, a new orally administered cephalosporin, was compared with those of cephalexin and cefaclor. BMY-28100 was the most active drug against Staphylococcus aureus (MIC for 90% of strains tested [MIC90], 1.0 microgram/ml), streptococci (MIC90S, less than or equal to 0.125 microgram/ml), and Klebsiella pneumoniae (MIC90, 2 micrograms/ml). The drug was active against Haemophilus influenzae and gonococci but not against other organisms generally resistant to cephem antibiotics.

In vitro activity of CI-934, a new quinolone antimicrobial, against gram-positive bacteria.

The in vitro activity of CI-934, a new quinolone antimicrobial, was compared with that of ciprofloxacin against selected gram-positive bacteria. Concentrations of CI-934 required to inhibit 90% of strains (MIC90) were twofold to eightfold lower than those of ciprofloxacin. With the exception of Streptococcus faecium, all isolates were inhibited by CI-934 at concentrations less than or equal to 1.0 microgram/ml.

In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic.

The in vitro activity of LY 146032, a cyclic lipopeptide antibiotic belonging to the class of agents designated A21978C, was compared with those of vancomycin, cefpirome, cefotaxime, and clindamycin against selected gram-positive bacteria. The new drug inhibited all staphylococcal isolates, including methicillin-resistant strains, at concentrations of less than or equal to 1.0 microgram/ml. The activity of LY 146032 was comparable to that of vancomycin against most streptococci, but the latter demonstrated greater potency against Streptococcus faecium and penicillin-resistant strains of pneumococci and viridans group streptococci. LY 146032 was markedly less active than vancomycin against Listeria monocytogenes (MICs for 90% of strains tested, 16 and 1.0 microgram/ml, respectively). The activity of LY 146032 was enhanced as the concentration of calcium in the test medium was increased. MBCs were within eightfold of the MIC for each of 12 strains tested. In a rat model of enterococcal endocarditis, the administration of LY 146032 resulted in increased survival and a reduction in the bacterial titer within cardiac vegetations compared with untreated control animals.

In vitro activities of the quinolone antimicrobial agents A-56619 and A-56620.

The in vitro activities of two new quinolone antimicrobial agents, A-56619 and A-56620, were compared with those of norfloxacin, ciprofloxacin, and other antimicrobial agents. The activity of A-56620 was comparable to that of ciprofloxacin against Escherichia coli, Enterobacter cloacae, and Aeromonas hydrophila (MICs for 90% of the strains were less than or equal to 0.06 micrograms/ml); Acinetobacter anitratus and Staphylococcus aureus (MIC for 90% of the strains was 0.5 micrograms/ml); and most streptococci. Against other gram-negative strains, A-56620 demonstrated activity comparable to that of norfloxacin, but the new drug was two to eight times more active than norfloxacin against gram-positive isolates. A-56620 was more active than A-56619 against most gram-negative organisms tested. Of the members of the family Enterobacteriaceae examined, 88% were inhibited by A-56619 and 99% by A-56620 at concentrations of less than or equal to 1.0 microgram/ml. By time-kill methods, the new quinolones were bactericidal against gram-negative bacilli during the first 6 h of incubation, but against S. aureus and enterococci the drugs were primarily bacteriostatic during this period. The frequency of spontaneous resistance to 10 micrograms of these drugs per ml was less than 10(-8) for all species tested except E. cloacae, but by serial passage through incremental concentrations of the antimicrobial agents, colonies many-fold more resistant than the initial isolate could be selected. However, resistance to concentrations of the drug greater than 100 micrograms/ml remained stable after passage on antibiotic-free media in only 1 of 35 strains tested.

In vitro activity of Sch 34343 against enterococci and other gram-positive bacteria.

The in vitro activity of Sch 34343, a new penem antibiotic, was compared with those of imipenem, vancomycin, and eight other antibiotics against gram-positive bacteria. Ninety percent of methicillin-susceptible Staphylococcus aureus and penicillin-susceptible streptococcal isolates were inhibited by Sch 34343 at concentrations of less than or equal to 0.125 micrograms/ml. Listeria monocytogenes isolates were susceptible to the penem at concentrations of less than or equal to 0.25 micrograms/ml. Penicillin-resistant pneumococci and viridans streptococci were relatively resistant to Sch 34343 (MIC for 90% of the isolates, 4 micrograms/ml), as were methicillin-resistant strains of S. aureus (MIC for 90% of the isolates, greater than or equal to 256 micrograms/ml). All 48 strains of Streptococcus faecalis were inhibited by concentrations of less than or equal to 8 micrograms of the drug per ml. Combinations of Sch 34343 with gentamicin demonstrated bactericidal synergism against 5 of 10 enterococcal strains tested in broth media and against 6 of 10 strains tested in 50% pooled human serum. The serum protein binding of Sch 34343 was ca. 65%. The antibacterial activity of Sch 34343 remained stable after 24 h of incubation at 37 degrees C in water or Dextrose-Phosphate broth. However, 63% of bioassayable activity was lost after 24 h of incubation at 37 degrees C in 50% human serum buffered with HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) (pH 7.4).